To the synthetic organic or polymer chemist, simple methods for forming carbon-carbon bonds are extremely important and valuable tools. One method of C—C bond formation that has proved particularly useful is transition-metal catalyzed olefin metathesis. “Olefin metathesis,” as is understood in the art, refers to the metal-catalyzed redistribution of carbon-carbon bonds. See Trnka and Grubbs (2001) Acc. Chem. Res. 34:18-29. Over two decades of intensive research effort has culminated in the discovery of well-defined ruthenium and osmium carbenes that are highly active olefin metathesis catalysts and stable in the presence of a variety of functional groups.
These ruthenium and osmium carbene complexes have been described in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108, 5,969,170, 6,111,121, and 6,211,391 to Grubbs et al., assigned to the California Institute of Technology. The ruthenium and osmium carbene complexes disclosed in these patents all possess metal centers that are formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated. These catalysts are of the general formula (I)
where M is a Group 8 transition metal such as ruthenium or osmium, X and X′ are anionic ligands, L and L′ are neutral electron donors, and R and R′ are specific substituents, e.g., one may be H and the other may be a substituted or unsubstituted hydrocarbyl group such as phenyl or C═C(CH3)2. Such complexes have been disclosed as useful in catalyzing a variety of olefin metathesis reactions, including ring opening metathesis polymerization (“ROMP”), ring closing metathesis (“RCM”), acyclic diene metathesis polymerization (“ADMET”), ring-opening metathesis (“ROM”), and cross-metathesis (“CM” or “XMET”) reactions.
For the most part, such metathesis catalysts have been prepared with phosphine ligands, e.g., triphenylphosphine or dimethylphenylphospine, exemplified by the well-defined, metathesis-active ruthenium alkylidene complexes (II) and (III)
wherein “Cy” is a cycloalkyl group such as cyclohexyl or cyclopentyl. See U.S. Pat. No. 5,917,071 to Grubbs et al. and Trnka and Grubbs, cited supra. These compounds are highly reactive catalysts useful for catalyzing a variety of olefin metathesis reactions, and are tolerant of many different functional groups. However, as has been recognized by those in the field, the compounds display low thermal stability, decomposing at relatively low temperatures. Jafarpour and Nolan (2000) Organometallics 19(11):2055-2057.
Recently, however, significant interest has focused on the use of N-heterocyclic carbene ligands as superior alternatives to phosphines. See, e.g., Trnka and Grubbs, supra; Bourissou et al. (2000) Chem. Rev. 100:39-91; Scholl et al. (1999) Tetrahedron Lett. 40:2247-2250; Scholl et al. (1999) Organic Lett. 1(6):953-956; and Huang et al. (1999) J. Am. Chem. Soc. 121:2674-2678. N-heterocyclic carbene ligands offer many advantages, including readily tunable steric bulk, vastly increased electron donor character, and compatibility with a variety of metal species. In addition, replacement of one of the phosphine ligands in these complexes significantly improves thermal stability. The vast majority of research on these carbene ligands has focused on their generation and isolation, a feat finally accomplished by Arduengo and coworkers within the last ten years (see, e.g., Arduengo et al. (1999) Acc. Chem. Res. 32:913-921). Representative of these second generation catalysts are the four ruthenium complexes (IVA), (IVB), (VA) and (VB):
In the above structures, Cy is as defined previously, “IMes” represents 1,3-dimesityl-imidazol-2-ylidene
and “IMesH2” represents 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene

Other complexes formed from N-heterocyclic carbene ligands are also known.
These transition metal carbene complexes, particularly those containing a ligand having the 4,5-dihydroimidazol-2-ylidene structure, such as in IMesH2, have been found to address a number of previously unsolved problems in olefin metathesis reactions, particularly cross-metathesis reactions. These problems span a variety of reactions and starting materials. The following discussion focuses on representative problems in the art that have now been addressed by way of the present invention.
Use of Olefinic Phosphonates and Other Functionalized Olefins as Cross-Metathesis Reactants: Olefins that contain phosphonate functionality are used extensively in synthetic organic chemistry. For example, allylic phosphonates are employed in the preparation of dienes and polyenes by Horner-Emmons olefination, providing products with improved stereoselectivity as compared to the corresponding phosphonium salts; see Crombie et al. (1969) J. Chem. Soc., Chem. Commun. at 1024; and Whang et al. (1992) J. Org. Chem. 56 :7177. The reaction of organic halides with trialkyl phosphites (Michaelis-Arbuzov reaction) is used primarily for the synthesis of allylphosphonates; see Bhattacharya et al. (1981) Chem. Rev. 81:415. However, elimination and/or loss of olefin stereochemical integrity are often competitive with product formation. Palladium catalyzed cross-coupling of hydrogen phosphonates to conjugated dienes and allenes has also been developed, but requires high reaction temperatures and provide low regioselectivity in highly substituted phosphonates products. See Hirao et al. (1980) Tetrahedron Lett. 21:3595; Hirao et al. (1982) Bull. Chem. Soc. Jpn. 55: 909; Imamoto et al. (1990) J. Am. Chem. Soc. 112 :5244; Zhao et al. (2000) Organometallics 19:4196.
Vinylphosphonates are important synthetic intermediates and have been investigated as biologically active compounds. Vinylphosphonates have been used as intermediates in stereoselective synthesis of trisubstituted olefins and in heterocycle synthesis; see Shen et al. (2000) Synthesis, p. 99; Tago et al. (2000) Org. Lett. 2:1975; Kouno et al. (1998) J. Org. Chem. 63:6239; and Kouno et al. (2000) J. Org. Chem. 65:4326. The synthesis of vinylphosphonates has also been widely examined and a variety of non-catalytic approaches have been described in the literature. Recent metal-catalyzed methods include palladium catalyzed cross-coupling (see, e.g., Holt et al. (1989), Tetrahedron Lett. 30:5393; Han et al. (1996), J. Am. Chem. Soc. 118:1571; Kazankova et al. (1999), Tetrahedron Lett. 40:569; Okauchi et al. (1999), Tetrahedron Lett. 40:5337; Zhong et al. (2000), Synth. Commun. 30:273; and Han et al. (2000), J. Am. Chem. Soc. 122:5407) and Heck coupling of aryldiazonium salts with vinyl phosphonates (Brunner et al. (2000) Synlett. at p. 201), but are limited by the requirement of highly reactive functional groups in the substrates. Therefore, a more mild, general and stereoselective method for the synthesis of vinyl and allylphosphonates using commercially available starting materials would be quite valuable, and would provide an additional degree of orthogonality to the previously reported syntheses. An ideal such method would also be applicable in other contexts as well, for example in the synthesis of olefins substituted with functional groups other than phosphonates. The invention, in one embodiment, is directed to this pressing need in the art, and provides a method that not only accomplishes the aforementioned goals, but is also useful in a more generalized process for creating functional group diversity in a population of olefinic products prepared using cross-metathesis.
Cross-Metathesis of α-Halogenated Olefins and Synthesis of Directly Halogenated Olefins: Since the discovery of the olefin metathesis reaction in the 1950s, the metathesis of halogen-containing olefins has received very little attention. The metathesis of allyl bromide, allyl chloride, and related substrates with the heterogeneous Re2O7/Al2O3/Me4Sn catalyst system are among the few examples. Kawai et al. (1998) J. Mol. Catal. A 133:51; Bogolepova et al. (1992) Petrol. Chem. 32:461; Mol et al. (1979) J. Chem. Soc. Chem. Commun., at pp. 330-331 Nakamura et al. (1977) Chem. Lett., at p. 1127; Fridman et al. (1997) Doklady Akad. Nauk S.S.S.R. 234:1354. Most recently, the cross-metathesis of 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexene with terminal olefin and the dimerization of vinyl gem-difluorocyclopropane derivatives have been achieved using catalyst (VB). Chatterjee et al. (2000) J. Am. Chem. Soc. 122:3783; International Patent Publication No. WO 02/00590 to Grubbs et al.; Itoh et al. (2000) Org. Lett. 2:1431. In these cases, the substrates are challenging because of the electron-withdrawing nature of the pendent halogens. A particularly challenging situation arises when the olefin is directly halogenated, because the metathesis reaction will then involve a monohalo [M]=CXR or dihalo [M]=CX2 carbene complex as the propagating species (where X=halide), rather than the more usual alkylidene [M]=CR2 (where R═H, alkyl, aryl). To the best of applicants' knowledge, there has been only one report of metathesis involving directly halogenated olefins, namely the cross-metathesis of 1-chloro- and 1-bromoethylene with propylene using Re2O7/Al2O3/Me4Sn (Fridman et al. (1977) Doklady Akad. Nauk S.S.S.R. 234:1354).
Accordingly, there are very few methods available for the mild and selective synthesis of directly halogenated olefins, and in particular, directly fluorinated olefins. The present invention now provides a straightforward method for carrying out an olefin metathesis reaction using an α-halogenated olefin, which may be an α-fluorinated olefin, in order to provide a directly halogenated (e.g., fluorinated) olefinic product.
Catalyzed Cross-Metathesis of Highly Substituted Olefins, Including Geminal Disubstituted Olefins and Quaternary Allylic Olefins: In prior applications of olefin metathesis, particularly olefin cross-metathesis, there has been no method available for generation of highly substituted olefins, such as trisubstituted olefins (wherein the substituents may be the same or different) and olefins that contain quaternary carbons at the allylic position. Trisubstituted and quaternary allylic olefinic substituents are, of course, present in a diverse array of organic molecules, including pharmaceuticals, natural products, and functionalized polymers, and the difficulty in generating such compounds has been a substantial limitation. The methodology of the present invention overcomes this limitation and now provides an efficient and versatile way to synthesize 1,1,2-trisubstituted olefins as well as 1,2-disubstituted olefins containing one quaternary allylic carbon atom.
Stereoselective Synthesis of 1,2-Disubstituted Olefins Via Cross-Metathesis: Another limitation in known olefin metathesis reactions is that there is no general method for controlling the stereoselectivity of the newly formed olefins. In many cases, the more thermodynamically stable trans olefin geometry was selectively formed, with minimal, if any, of the cis olefin produced. See Blackwell et al. (2000), “New approaches to olefin cross-metathesis,” J. Am. Chem. Soc. 122(1):58-71; and Chatterjee et al. (2000), “Synthesis of functionalized olefins by cross and ring-closing metathesis,” J. Am. Chem. Soc. 122(15):3783-3784. The present invention also addresses this need in the art by providing a stereoselective method for synthesizing a 1,2-disubstituted olefin in primarily the cis configuration.